Using self-administration procedures, several different types of experiments are being conducted. The abuse liability of drugs are being assessed by comparing the rates and patterns of responding maintained by various drugs, including cocaine, nicotine and other psychomotor stimulants, benzodiazepines and other sedative/anxiolytics, morphine and other opioids. These studies will compare responding maintained under fixed-ratio, fixed-interval schedules and complex second-order schedules. The ability of pharmacological treatments and the development of tolerance/dependence to modify drug self-administration behavior and/or food maintained behavior is also being assessed. In addition to differences in pharmacological efficacy of drugs, it is clear that behavioral and environmental factors can modify the control that even highly efficacious drugs exert on behavior. The focus of experiments in the rhesus self-administration lab are to study the pharmacological, behavioral, and environmental variables involved in initiating and maintaining drug self-administration. Certain drugs, such as cocaine and other psychomotor stimulants generally function effectively as reinforcers under a variety of conditions. Other drugs such as benzodiazepines, some opioids, and caffeine, however, have been studied only under relatively limited conditions, and generally maintain low levels of responding. Parallel comparative studies in squirrel monkeys and humans in which subjects are given the opportunity to self-administer comparable doses of cocaine, morphine, nicotine and other drugs under similar behavioral schedules and experimental conditions provide a means to assess the generality of biological variables influencing drug self-administration. We have previously shown under a second-order schedule of drug self-administration, low doses of morphine can support self-administration in humans even though the subjects report no subjective effects of these drug doses. This result indicates that subjective reports of a drug effect may not be an important factor in the positive reinforcing effects of drugs of abuse. To further substantiate these findings, we are currently repeating these experiments. In addition, we are also testing subjects who administer low morphine doses with the opioid antagonist naltrexone to determine whether any physiological signs of precipitated withdrawal can be observed. Subjective reports will also taken during the withdrawal test to determine whether withdrawal may also occur independent of subjective report, or whether there is a closer match between the subjective reports and withdrawal than between self-administration and subjective reports.